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23 March 2017 CPMP/EWP/239/95 Rev. 1 Committee for Medicinal Products for Human Use (CHMP)

Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied, locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied, locally acting products containing known constituents. Draft

Draft agreed by Gastroenterology Working Party and Quality

October 2016

Working Party Draft agreed by Pharmacokinetics Working Party

February 2017

Adopted by CHMP for release for consultation

23 March 2017

Start of public consultation End of consultation (deadline for comments)

4 April 2017 30 September 2017

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This guideline builds upon the existing 'The Note for guidance on the clinical requirements for locally

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applied, locally acting products containing known constituents' (CPMP/EWP/239/95).

14 Comments should be provided using this template. The completed comments form should be sent to [email protected] 15 Keywords

Therapeutic equivalence, gastrointestinal, mouth, throat, locally applied and locally acting, in vitro, pharmacokinetic, equivalence, bioequivalence, guideline, CHMP

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An agency of the European Union

© European Medicines Agency, 2017. Reproduction is authorised provided the source is acknowledged.

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Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied, locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied, locally acting products containing known constituents

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Table of contents

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Executive summary ..................................................................................... 3

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1. Introduction (background) ...................................................................... 3

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2. Scope....................................................................................................... 3

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3. Legal basis and relevant guidelines ......................................................... 4

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4. Main guideline text .................................................................................. 4

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4.1. Types of locally acting, locally applied gastrointestinal products ................................. 4

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4.2. General requirements for demonstration of equivalence ............................................ 5

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4.3. Equivalence requirements in specific situations ........................................................ 6

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4.3.1. Products acting locally in the mouth and/or throat ................................................. 6

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4.3.2. Products acting locally in the stomach .................................................................. 8

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4.3.3. Products acting locally in the intestine .................................................................. 9

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4.3.4. Products acting locally in the rectum .................................................................. 11

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4.4. Requirements for additional strengths ................................................................... 12

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Executive summary

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This guideline defines the requirements that need to be fulfilled to waive clinical trials with clinical or

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pharmacodynamic endpoints in the demonstration of therapeutic equivalence for locally applied, locally

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acting gastrointestinal products. It also defines the in vivo bioequivalence studies and in vitro

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equivalence tests that are necessary.

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1. Introduction (background)

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This guideline refers to medicinal products that are applied locally and intended to exert their effect

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locally within the gastrointestinal (GI) tract. The assumption is that systemic action, if any, would be

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considered as an undesired effect.

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The Note for guidance on the clinical requirements for locally applied, locally acting products containing

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known constituents (CPMP/EWP/239/95) provides general recommendations on the clinical

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requirements for medicinal products with known active substances. According to this guideline, in order

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to demonstrate therapeutic equivalence, clinical trials are in principle considered necessary, but other

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models may be used or developed. Depending on the situation, human pharmacodynamic (PD) studies,

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local availability studies or, where appropriate, even animal or in vitro studies may be considered,

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provided that the respective methods/models are adequately qualified.

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During recent years the assessment of locally applied and locally acting products has evolved. It has

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been shown that alternative models (including in vitro and in vivo methods) may have a higher

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sensitivity than traditional clinical and PD endpoints to detect possible differences between medicinal

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products containing the same active substance. Also based on the experience with some of these

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alternative models, either individually or in combination, it is possible to compare directly or indirectly

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concentrations at the site of action. Therefore, therapeutic equivalence of locally applied, locally acting

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GI products could be demonstrated using these alternative models, provided they have been proven to

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be able to accurately reflect in vivo drug release and availability at the site of action. Furthermore, it

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has been recognised that the similarity of drug release and availability at the site of action are the

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major factors determining similar clinical responses for locally applied, locally acting medicinal products

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containing the same active substance. Therefore, in those cases where the in vitro tests or

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pharmacokinetic (PK) studies reflect in vivo drug release and availability at the site of action, clinical

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trials could be waived.

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The type of studies required to demonstrate equivalence should be decided taking into account the

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different characteristics of the different types of dosage forms acting in the GI tract.

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2. Scope

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This guideline focuses on the choice of in vitro equivalence tests and PK bioequivalence studies as

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suitable models for the demonstration of therapeutic equivalence for locally applied, locally acting GI

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products with immediate or modified release containing the same chemical entity. The choice has to be

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fully justified.

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The design of PD studies and therapeutic equivalence clinical trials depends on the respective

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therapeutic field. The corresponding guidelines should be taken into consideration and these types of

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studies and trials are outside of the scope of this guideline.

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The scope is limited to chemical entities. Recommendations for biologicals can be found in guidelines

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on similar biological medicinal products. Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied, locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied, locally act CPMP/EWP/239/95 Rev. 1

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3. Legal basis and relevant guidelines

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This guideline applies mainly to Marketing Authorisation Applications for human medicinal products

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submitted in accordance with the Directive 2001/83/EC as amended, under Art. 10(3) (hybrid

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applications). It may also be applicable to Marketing Authorisation Applications for human medicinal

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products submitted under Art. 8(3) (full applications), Art.10b (fixed combination), Art.10a (well-

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established use applications) of the same Directive, and for extension and variation applications in

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accordance with Commission Regulations (EC) No 1084/2003 and 1085/2003.

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This guideline should be read in conjunction with the Annex I of Directive 2001/83/EC as amended, as

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well as European and ICH guidelines for conducting clinical trials, including those on:

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Clinical requirements for locally applied, locally acting products containing known constituents

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(CPMP/EWP/239/95).

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Pharmacokinetic studies in man (Eudralex, Volume 3, 3CC3a).

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Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **).

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Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms

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(EMA/CPMP/EWP/280/96 Corr1).

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Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009).

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Requirements for clinical documentation for orally inhaled products (OIP) including the

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requirements for demonstration of therapeutic equivalence between two inhaled products for

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use in the treatment of Asthma and Chronic Obstructive Pulmonary Disease (COPD)

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(CPMP/EWP/4151/00 rev 1).

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The guideline should also be read in conjunction with relevant guidelines on pharmaceutical quality.

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The test products used in the equivalence study must be prepared in accordance with GMP regulations

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including Eudralex volume 4.

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Equivalence trials conducted in the EU/EEA have to be carried out in accordance with Directive

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2001/20/EC. Trials conducted outside of the Union and intended for use in a Marketing Authorisation

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Application in the EU/EEA have to be conducted to the standards set out in Annex I of the community

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code, Directive 2001/83/EC as amended.

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Companies may apply for CHMP Scientific Advice for specific queries and in particular, in case of

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narrow therapeutic index drugs.

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4. Main guideline text

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4.1. Types of locally acting, locally applied gastrointestinal products

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For the purpose of this guideline locally applied, locally acting products can be classified:

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1. According to the site of action, e.g.:

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a) In the mouth and/or throat (e.g. local analgesics or anaesthetics).

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b) In the stomach (e.g. antacids)

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c)

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In the intestine (e.g. anti-inflammatory and anti-motility agents) a.

Drugs that have a pharmacological, intracellular target

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b.

Drugs that have a target in the lumen or at the membrane surface

2. According to their mechanism of action, e.g.: a) Chelating compounds of the GI fluids/milieu or binding to targets in the lumen (e.g. phosphate

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or bile).

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b) Adding endogenous compounds (e.g. pancreatin)

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c)

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d) Exerting a physical effect (e.g. osmotic / bulking agents)

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e) Binding to receptors or targets in the intestinal mucosa (e.g. loperamide, corticosteroids, 5-

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Changing physicochemical conditions (e.g. antacids)

ASA) 3. According to their biopharmaceutical and PK properties:

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a) Absorbable drugs

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b) Non-absorbable drugs

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4. According to their pharmaceutical form:

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a) Immediate release formulations

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a) solutions

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b) non-solutions

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b) Modified release formulations 5. According to the state of the drug in the dosage form:

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a) A solute in solution (e.g. solution, gel)

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b) A solute in solid pharmaceutical form (e.g. lozenge)

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c)

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d) A solid in solid pharmaceutical form (e.g. tablet)

A solid in liquid (e.g. cream, ointment, suspension)

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4.2. General requirements for demonstration of equivalence

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General assessment of equivalence applies to locally applied, locally acting GI products to be approved

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either as a generic/hybrid or as a reformulated product, i.e. therapeutic equivalence should ensure

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equivalence in terms of efficacy and safety. In principle, clinical trials with clinical endpoints are

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considered necessary to demonstrate therapeutic equivalence, but alternative approaches may be used

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provided they have a sound justification and appropriate qualification. In vitro test(s)/model(s) should

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be validated (e.g. in line with ICH Q2 (R1)) before use and they should reflect the particular (unique)

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characteristics of the pharmaceutical form for which equivalence is being claimed. A comprehensive

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and sound justification for the chosen in vitro test(s)/model(s) should be provided.

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In order to claim that an alternative model is reflecting in vivo drug release and availability at the site

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of action, the applicant should justify the relevance for the therapeutic effect and the higher or similar

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sensitivity based on their own experimental data or literature data.

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The sensitivity of the PK endpoints/in vitro methods following administration of different doses of the

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reference product should be well established, e.g. based on literature data or on a pilot study. Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied, locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied, locally act CPMP/EWP/239/95 Rev. 1

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Alternatively, it could be addressed as part of the study designed to demonstrate bioequivalence with

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the use of additional groups with different doses of the reference formulation to ensure that the dose

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used for the bioequivalence comparison is sensitive and sufficiently discriminative to detect potential

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differences between formulations.

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In general, the following hierarchy from simpler to more complex bodies of data required to

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demonstrate equivalence should be followed: pharmaceutical quality data alone, pharmaceutical

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quality data + in vitro model, pharmaceutical quality data + in vivo PK data and pharmaceutical quality

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data + in vitro model + in vivo PK data. The approach taken should be fully justified. In order to use

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these alternative methods, it should be taken into account that product quality (as critical quality

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attributes) is an essential part, as is the method of administration. For instance, the requirements for

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demonstration of in vivo PK bioequivalence may be waived under a specific set of circumstances when,

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for example, the test and reference products are a solution, the products possess similar critical quality

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attributes and are qualitatively and quantitatively similar, and the method of administration is the

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same. In order to address systemic safety, even if clinical equivalence is demonstrated with a PD

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approach, data on the extent of absorption may be required, or their lack should be justified. If this

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requires a bioequivalence study, then the 90% confidence interval range for the ratio test/reference of

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the PK parameters of interest should not exceed the upper limit of the acceptance range as described

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in the guideline on the investigation of bioequivalence.

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In certain cases a PK bioequivalence study may also be indicative of therapeutic equivalence (e.g.

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drugs that are mainly absorbed from the site of action). In these cases the usual acceptance criteria

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for bioequivalence should be applied.

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Local safety and tolerability should be addressed. Ideally, the same excipients and amounts used in the

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reference products should be selected for the test products. Differences in inactive ingredients,

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whether known or unknown, may require additional comparative tolerability studies.

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The list of in vitro models included in this guideline is not exhaustive and other may be submitted, if

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justified.

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4.3. Equivalence requirements in specific situations

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4.3.1. Products acting locally in the mouth and/or throat

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A large variety of dosage forms can be administered for local action in the mouth and/or the throat,

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e.g. solutions, suspensions, elixirs, powders, tablets, lozenges, troches, gels, ointments, buccal sprays,

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etc. The general principles outlined in this guideline are applicable to all these products. Further

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detailed guidance can be obtained in other guidelines that may be more applicable to certain dosage

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forms (e.g. gels and ointments as topical products and buccal sprays as similar to nasal sprays).

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Solutions

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If the test product is a solution at time of administration and contains an active substance in the same

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concentration as an approved solution, studies supporting equivalent efficacy and safety may be

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waived. However, excipient composition should be critically reviewed since excipients may affect local

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residence time (e.g. palatability, surface tension, viscosity, etc.), in vivo solubility (e.g. co-solvents) or

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in vivo stability of the active substance. An equivalence study should be conducted, unless the

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differences in the amounts of these excipients can be adequately justified by reference to other data

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and taking account of Appendix II of the guideline on the investigation of bioequivalence.

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In those cases where the test product is an oral solution that is intended to be equivalent to another Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied, locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied, locally act CPMP/EWP/239/95 Rev. 1

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immediate release oral dosage form, equivalence studies are required.

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Non-solutions

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If the test product is not a solution (e.g. solid dosage form), demonstration of equivalent availability at

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the site of action by means of Cmax and AUC of saliva concentration-time profiles can be considered as

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a surrogate of therapeutic equivalence. Local availability studies are feasible because direct sampling in

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the site of action is often possible (i.e. saliva). Therefore, a comparative local in vivo availability study

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with sampling of saliva is a possible approach despite its inherent variability. In accordance with the

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standard accepted methods of assessment of bioequivalence the maximum concentration (Cmax), the

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area under the curve (AUC) and the time to Cmax (Tmax) should be compared. Equivalence may be

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concluded if the 90 % confidence interval for each parameter lies within the acceptance range of 80.00

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to 125.00%.

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In those cases where it is justified that the drug is released from the dosage form as a solution due to

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its high solubility and not as a suspension, it is possible to assess indirectly the local availability or the

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amount released by assessing the amount remaining in the dosage form at selected time points. In

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addition, in those cases where it is justified that the drug is dispersed homogeneously in the dosage

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form, the amount remaining in the dosage form can be estimated by weight. Equivalence may be

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concluded as for in vitro dissolution tests as outlined in Appendix 1 of the guideline on the investigation

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of bioequivalence. Dissolution profile similarity should be assessed based on an acceptance range of

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±10% in accordance to the acceptance range (≥50) of the f2 similarity factor.

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In those cases where concentrations are not measured directly at the site of action (e.g.

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concentrations in saliva), it is necessary to review critically the excipient composition to ensure that

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differences in excipients do not affect local residence time (e.g. palatability, surface tension, viscosity,

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etc.), in vivo solubility (e.g. co-solvents) and/or in vivo stability of the active substance.

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Plasma levels cannot in many cases be used directly as a surrogate of therapeutic equivalence because

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it is necessary to distinguish between plasma levels obtained from local absorption at the site of action

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in the upper digestive tract (e.g. mouth) and those due to absorption in the other parts of the GI tract

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(e.g. the intestine). Only if absorption in other parts of the GI tract can be disregarded (e.g. by use of

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activated charcoal), can the plasma levels be considered as reflective of the concentrations at the site

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of action and would be acceptable. However, it should be ensured that activated charcoal is able to

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block absorption from the intestine to negligible levels with respect to the systemic levels obtained by

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absorption through the site of action.

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For the time being, usual comparative in vitro dissolution methodology is not considered indicative of

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in vivo dissolution in the mouth and/or throat.

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Decision tree for products acting locally in the mouth and/or throat

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4.3.2. Products acting locally in the stomach

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Solutions

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See Section 4.3.1. In addition, particular consideration should be given to excipients that may affect

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gastric emptying, absorption (e.g. pH), in vivo solubility (e.g. co-solvents) or in vivo stability of the

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active substance (e.g. pH). In general, Appendix II of the guideline on the investigation of

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bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**) and the drug substance BCS classification

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should be considered.

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Non-solutions

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For antacids, in vitro methodology based on dynamic and static neutralizing tests is considered a

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surrogate methodology for therapeutic equivalence demonstration. It is anticipated that a number of

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different in vitro methods may be used to demonstrate similarity between the reference and test

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products. The Applicant should justify the selected dynamic and static neutralizing tests, along with the

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in vitro parameters, especially that the proposed end-points are clinically relevant. The in vitro

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methods should use widely accepted apparatus or, if a new method is used, should be suitably

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validated. In vitro similarity should be assessed with a ±10% acceptance range, unless otherwise

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justified (e.g. by assessing the difference between batches of the reference product).

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In those cases where some degree of drug absorption and systemic bioavailability is observed, a

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bioequivalence study is required in order to address systemic safety. The systemic safety Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied, locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied, locally act CPMP/EWP/239/95 Rev. 1

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bioequivalence study could be waived if a BCS biowaiver were applicable according to the criteria

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described in the guideline on the investigation of bioequivalence. Plasma levels cannot be used, in

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principle, as a surrogate of equivalence in efficacy for products acting locally in the stomach exclusively

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because the site of action in the stomach is different to the site of absorption in the intestine.

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Hypothetically, two products with a different release and dissolution, but within the gastric residence

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time, may exhibit a similar plasma concentration – time profile since the gastric emptying is the rate-

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limiting factor for absorption.

256 Decision tree for products acting locally in the stomach

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4.3.3. Products acting locally in the intestine

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Solutions

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See Section 4.3.2. In addition, particular consideration should be given to excipients that may affect GI

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transit (e.g. sorbitol, mannitol, etc.), absorption (e.g. surfactants or excipients that may affect

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transport proteins), in vivo solubility (e.g. co-solvents) or stability of the active substance.

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Bioequivalence studies based on systemic exposure might be employed to compare test and reference

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products if some degree of systemic bioavailability is observed.

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Non-solutions

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For those products with a mechanism of action based on binding to components of the GI milieu

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through the whole intestine (e.g. cholestyramine, colestipol, calcium acetate, sevelamer) in vitro

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studies based on their binding capacity (e.g. in-vitro equilibrium and dynamic binding studies) are

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considered acceptable surrogates for the assessment of efficacy, as long as excipients are not critical

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and disintegration and dissolution profiles in the physiological pH range are similar. Similarly, for those Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied, locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied, locally act CPMP/EWP/239/95 Rev. 1

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products with a bulking effect demonstration of similarity by means of in vitro tests (e.g. swelling,

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viscosity) is considered as demonstration of therapeutic equivalence. In vitro similarity should be

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assessed with a ±10% acceptance range, unless otherwise justified.

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For immediate release products containing a highly soluble drug, a BCS biowaiver is possible based on

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the criteria defined in Appendix III of the guideline on the investigation of bioequivalence. However, in

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those drugs without systemic bioavailability (i.e. BCS class III) very rapid dissolution is not essential

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and rapid dissolution may be acceptable.

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If the conditions to apply for a BCS biowaiver are not fulfilled and some degree of systemic

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bioavailability is observed, bioequivalence studies based on plasma levels usually in fed and fasting

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state could be used as a surrogate of equivalence in efficacy and systemic safety because the site of

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action is the site of absorption for drugs acting inside the gastrointestinal membrane. For drugs acting

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in the lumen or the luminal side of the membrane bioequivalence studies based on plasma levels

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usually in fasting and fed state could also be used as a surrogate of equivalence, if absorption is not

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saturated (demonstrated e.g. by means of a dose-proportionality study). It can be assumed that when

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the rate and extent of absorption of the drug is comparable, distribution of drug within the different

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zones of the intestine is comparable. Bioequivalence studies in fasting and fed state are usually

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required, even for products that are recommended to be taken in fasting state only, because locally

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acting drugs generally have low permeability and remain in the intestinal lumen for a prolonged period.

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Therefore, they are expected to interact with food during their intestinal transit.

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For modified release products containing a drug being absorbed and showing systemic bioavailability,

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bioequivalence studies based on plasma levels could also be used as a surrogate of equivalence in

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efficacy and systemic safety because the systemic absorption occurs at the site of release. Partial AUC

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assessment can help to distinguish absorption caused by an early release and absorption from release

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at the site of action, if:

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a) absorption is not saturated at the relevant dose (shown e.g. by means of a dose-proportionality

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study for all the PK parameters of interest);

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b) test and reference are the same dosage form;

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c)

test and reference exhibit similar in vitro dissolution profiles in a battery of state-of-the-art

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experiments (not only in the QC media and buffers at pH 1.2, 4.5 and 6.8, but also in vitro

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methods simulating intraluminal pH-conditions and residence times in the human GI tract, e.g.

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tests in the reciprocating cylinder apparatus simulating “average” fasted subjects and also a range

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of “patient-specific” patterns of pH-conditions and passage times with continuous and

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discontinuous passage through the small intestine);

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d) partial exposures and their corresponding absorption sites are well justified.

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The requirements defined in the ‘Guideline on the Pharmacokinetic and Clinical Evaluation of Modified

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Release Dosage Forms’ should be applied. Bioequivalence should be demonstrated in single dose

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studies in fasting and fed state and, in case of prolonged release products with significant

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accumulation, also in a multiple dose study. Partial AUCs (early and late partial AUCs as defined by

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predefined, well justified cut-off points) should be used as primary PK endpoint in both types of single

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dose studies, even in case of significant accumulation when a multiple dose study is required.

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Decision tree for products acting locally in the intestine

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4.3.4. Products acting locally in the rectum

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A large variety of dosage forms can be administered for local action in the rectum, e.g. enemas in

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solution or suspension, suppositories, gels, foams, etc. The general principles outlined in this guideline

318

are applicable to all these products. Further detailed guidance can be obtained in other guidelines that

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may be more applicable to certain dosage forms (e.g. gels and foams as topical products).

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Solutions

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See section 4.3.1. In addition, particular consideration should be given to excipients that may affect

322

local tolerance, local residence time (e.g. surface tension, viscosity, etc.) in vivo solubility (e.g. co-

323

solvents) or in vivo stability of the active substance.

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Non-solutions

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If the test product is not a solution (e.g. solid dosage form), demonstration of equivalent drug release

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and availability at the site of action can be considered as surrogate of therapeutic equivalence.

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In those cases where systemic bioavailability is observed, a PK bioequivalence study is required in

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order to address systemic safety. In such cases plasma levels could also be used as a surrogate of

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equivalence in efficacy for products acting locally in the rectum and the colon (e.g. enemas) if the drug

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is absorbed from the site of action. Then, plasma levels reflect the drug release and availability close to

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the site of action. Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied, locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied, locally act CPMP/EWP/239/95 Rev. 1

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In any case, excipient composition should be critically reviewed since excipients may affect tolerability,

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systemic absorption, local residence time (e.g. surface tension, viscosity, etc.), in vivo solubility (e.g.

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co-solvents) or in vivo stability of the active substance. An equivalence study should be conducted,

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unless the differences in the amounts of these excipients can be adequately justified by reference to

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other data.

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Decision tree for products acting locally in the rectum

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340 341

4.4. Requirements for additional strengths

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The conditions that additional strengths have to fulfil in order to be waived depend on the type of

343

product (e.g. immediate release or modified release oral dosage forms). In principle these

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requirements are similar to those for systemically acting products as described in the guideline on the

345

investigation of bioequivalence and the guideline on the pharmacokinetic and clinical evaluation of

346

modified release dosage forms.

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In those cases where the reference product has different strengths and equivalence is shown by means

348

of in vivo studies (e.g. bioequivalence PK studies, i.e. pharmaceutical quality data + in vivo PK data),

349

bioequivalence should be shown with the most sensitive strength to detect possible differences.

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Additional strengths may be waived from this in vivo demonstration ("additional strength biowaiver") if

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certain conditions are met as described in the ‘Guideline on the investigation of bioequivalence’.

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In those cases where the reference product has different strengths and equivalence is shown by means

353

of pharmaceutical quality data (e.g. comparison of excipient composition) or pharmaceutical quality

354

data + in vitro data (e.g. comparative dissolution profiles in a BCS biowaiver for a class III containing

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product), equivalence should be shown for each individual strength of the test product with respect to

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the corresponding strength of the reference product, instead of using the "additional strength

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biowaiver", i.e. a comparison between the different strengths of the test product.

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In those cases where the reference product has different strengths and equivalence is shown by means

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of pharmaceutical quality data + in vitro data + in vivo PK data (e.g. prolonged release solid oral Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied, locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied, locally act CPMP/EWP/239/95 Rev. 1

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dosage form), additional strengths may be waived from the in vivo demonstration ("additional strength

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biowaiver") if certain conditions are met as described above, but, in addition, equivalence to the

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corresponding strength of the reference product in the pharmaceutical quality data and the in vitro

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data should be shown for each individual strength.

Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied, locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied, locally act CPMP/EWP/239/95 Rev. 1

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Draft guideline on equivalence studies for the demonstration of ...

Mar 23, 2017 - pharmacodynamic endpoints in the demonstration of therapeutic equivalence for locally applied, locally. 41 acting gastrointestinal products.

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